Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

doi:10.1093/jnci/djx001

Randomized Controlled Trial

. 2017 Sep 1;109(9):djx001.

doi: 10.1093/jnci/djx001.

Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

Celia Byrne¹, Giske Ursin², Christopher F Martin³, Jennifer D Peck⁴, Elodia B Cole⁵, Donglin Zeng³, Eunhee Kim⁶, Martin D Yaffe⁷, Norman F Boyd⁸, Gerardo Heiss³, Anne McTiernan⁹, Rowan T Chlebowski¹⁰, Dorothy S Lane¹¹, JoAnn E Manson¹², Jean Wactawski-Wende¹³, Etta D Pisano⁵

Affiliations

¹ Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
² Cancer Registry of Norway, Institute of Population Based Cancer Research, Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway and Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
³ University of North Carolina, Chapel Hill, NC, USA.
⁴ The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA.
⁶ National Institutes of Health, Bethesda, MD, USA.
⁷ Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
⁸ Ontario Cancer Institute, Toronto, Ontario, Canada.
⁹ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁰ Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹¹ Stony Brook School of Medicine, Stony Brook, NY, USA.
¹² Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ University at Buffalo, State University of New York, Buffalo, NY, USA.

PMID: 28376149
PMCID: PMC6059178
DOI: 10.1093/jnci/djx001

Randomized Controlled Trial

Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

Celia Byrne et al. J Natl Cancer Inst. 2017.

. 2017 Sep 1;109(9):djx001.

doi: 10.1093/jnci/djx001.

Authors

Affiliations

¹ Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
² Cancer Registry of Norway, Institute of Population Based Cancer Research, Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway and Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
³ University of North Carolina, Chapel Hill, NC, USA.
⁴ The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA.
⁶ National Institutes of Health, Bethesda, MD, USA.
⁷ Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
⁸ Ontario Cancer Institute, Toronto, Ontario, Canada.
⁹ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁰ Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹¹ Stony Brook School of Medicine, Stony Brook, NY, USA.
¹² Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ University at Buffalo, State University of New York, Buffalo, NY, USA.

PMID: 28376149
PMCID: PMC6059178
DOI: 10.1093/jnci/djx001

Abstract

Background: Estrogen plus progestin therapy increases both mammographic density and breast cancer incidence. Whether mammographic density change associated with estrogen plus progestin initiation predicts breast cancer risk is unknown.

Methods: We conducted an ancillary nested case-control study within the Women's Health Initiative trial that randomly assigned postmenopausal women to daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placebo. Mammographic density was assessed from mammograms taken prior to and one year after random assignment for 174 women who later developed breast cancer (cases) and 733 healthy women (controls). Logistic regression analyses included adjustment for confounders and baseline mammographic density when appropriate.

Results: Among women in the estrogen plus progestin arm (97 cases/378 controls), each 1% positive change in percent mammographic density increased breast cancer risk 3% (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01 to 1.06). For women in the highest quintile of mammographic density change (>19.3% increase), breast cancer risk increased 3.6-fold (95% CI = 1.52 to 8.56). The effect of estrogen plus progestin use on breast cancer risk (OR = 1.28, 95% CI = 0.90 to 1.82) was eliminated in this study, after adjusting for change in mammographic density (OR = 1.00, 95% CI = 0.66 to 1.51).

Conclusions: We found the one-year change in mammographic density after estrogen plus progestin initiation predicted subsequent increase in breast cancer risk. All of the increased risk from estrogen plus progestin use was mediated through mammographic density change. Doctors should evaluate changes in mammographic density with women who initiate estrogen plus progestin therapy and discuss the breast cancer risk implications.

Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.

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Figures

**Figure 1.**
Distribution of change in mammographic density from baseline to at least one year after random assignment within participants from the placebo arm of the Women’s Health Initiative. The mean change in percent mammographic density declined by 0.05%, with a median change in mammographic density of 0.0% and a standard deviation of 6.36.

**Figure 2.**
Distribution of change in mammographic density from baseline to at least one year after random assignment within participants from the estrogen plus progestin arm of the Women’s Health Initiative. The mean change in percent mammographic density increased by 9.73%, with a median change in mammographic density of 6.02% and a standard deviation of 12.80.

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References

1. Rossouw JE, Anderson GL, Prentice RL, et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. - PubMed
1. Chlebowski RT, Hendrix SL, Langer RD, et al.Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA. 2003;289(24):3243–3253. - PubMed
1. Hersh AL, Stefanick ML, Stafford RS.. National use of postmenopausal hormone therapy: Annual trends and response to recent evidence. JAMA. 2004;291(1):47–53. - PubMed
1. Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske K.. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med. 2004;140(3):184–188. - PubMed
1. Hing E, Brett KM.. Changes in US prescribing patterns of menopausal hormone therapy, 2001–2003. Obstet Gynecol. 2006;108(1):33–40. - PubMed

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[1] Rossouw JE, Anderson GL, Prentice RL, et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. - PubMed

[2] Rossouw JE, Anderson GL, Prentice RL, et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. - PubMed

[3] Chlebowski RT, Hendrix SL, Langer RD, et al.Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA. 2003;289(24):3243–3253. - PubMed

[4] Chlebowski RT, Hendrix SL, Langer RD, et al.Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA. 2003;289(24):3243–3253. - PubMed

[5] Hersh AL, Stefanick ML, Stafford RS.. National use of postmenopausal hormone therapy: Annual trends and response to recent evidence. JAMA. 2004;291(1):47–53. - PubMed

[6] Hersh AL, Stefanick ML, Stafford RS.. National use of postmenopausal hormone therapy: Annual trends and response to recent evidence. JAMA. 2004;291(1):47–53. - PubMed

[7] Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske K.. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med. 2004;140(3):184–188. - PubMed

[8] Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske K.. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med. 2004;140(3):184–188. - PubMed

[9] Hing E, Brett KM.. Changes in US prescribing patterns of menopausal hormone therapy, 2001–2003. Obstet Gynecol. 2006;108(1):33–40. - PubMed

[10] Hing E, Brett KM.. Changes in US prescribing patterns of menopausal hormone therapy, 2001–2003. Obstet Gynecol. 2006;108(1):33–40. - PubMed

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Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

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Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

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